Page 21 - Tyrosine-Based Bioconjugations - Jorick Bruins
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turn lowers the barrier of activation for (3+2) cycloadditions, resulting in the spontaneous reaction known as strain-promoted azide–alkyne cycloaddition (SPAAC). Finally, it is noteworthy to mention that BCN can perform inverse-electron demand cycloaddition with azides (IED SPAAC), in particular when an electron-poor azide (e.g. 2,6-difluorophenyl azide) is used.68 The use of electron-poor azides can in fact speed up the reaction (i.e. 2,6-difluorophenyl azide increased the reaction rate of SPAAC with BCN by a factor 11), whereas for other commonly used strained alkynes such as DIBAC (aka DBCO) these electron-poor azides reduce the reaction rate (i.e. 2,6-difluorophenyl azide decreased the reaction rate of by a factor two).
Scheme 2. Schematic representations of (A) azide-bearing phenylalanine and SPAAC with BCN-bearing probes, and (B) TCO-bearing lysine and its IEDDA with MeTz-bearing probe.
Inverse-electron demand Diels-Alder reactions (IEDDA) are most prominent with 1,2,4,5- tetrazines, of which methyltetrazine (20) is a stable and widely used variant.69 BCN can also perform IEDDA with methyltetrazines at a respectable second-order reaction rate of 80 M-1 s-1,70 it is however significantly slower than the trans-cyclooctene (TCO) cycloaddition with a rate of
General Introduction
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